This is an application under 35 U.S.C. 371 of PCT/GB99/01799 and claims priority from Great Britain Application No. 9812038.9, filed Jun. 4, 1998.
The present invention relates to tetrahydroindolone derivatives, pharmaceutical compositions comprising them and to their use in therapy. More particularly, this invention is concerned with substituted derivatives which are ligands for GABAA receptors, in particular for GABAA xcex15 receptors and are therefore useful in therapy particularly where cognition enhancement is required.
Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: (1) GABAA receptors, which are members of the ligand-gated ion channel superfamily; and (2) GABAB receptors, which may be members of the G-protein linked receptor superfamily. Since the first cDNAs encoding individual GABAA receptor subunits were cloned the number of known members of the mammalian family has grown to thirteen (six xcex1 subunits, three xcex2 subunits, three xcex3 subunits and one xcex4 subunit). It may be that further subunits remain to be discovered; however, none has been reported since 1993.
Although knowledge of the diversity of the GABAA receptor gene family represents a huge step forward in our understanding of this ligand-gated ion channel, insight into the extent of subtype diversity is still at an early stage. It has been indicated that an xcex1 subunit, xcex1 xcex2 subunit and a xcex3 subunit constitute the minimum requirement for forming a fully functional GABAA receptor expressed by transiently transfecting cDNAs into cells. As indicated above, a xcex4 subunit also exists, but is apparently uncommon in the native receptor.
Studies of receptor size and visualisation by electron microscopy conclude that, like other members of the ligand-gated ion channel family, the native GABAA receptor exists in pentameric form. The selection of at least one xcex1, one xcex2 and one xcex3 subunit from a repertoire of thirteen allows for the possible existence of more than 10,000 pentameric subunit combinations. Moreover, this calculation overlooks the additional permutations that would be possible if the arrangement of subunits around the ion channel had no constraints (i.e. there could be 120 possible variants for a receptor composed of five different subunits).
Receptor subtype assemblies which do exist include xcex11xcex22xcex32, xcex12xcex22/3xcex32, xcex13xcex2xcex32/3, xcex12xcex2xcex31, xcex15xcex23xcex32/3, xcex16xcex2xcex32, xcex16and xcex14xcex2xcex4. Subtype assemblies containing an xcex11 subunit are present in most areas of the brain and account for over 40% of GABAA receptors in the rat. Subtype assemblies containing xcex12 and xcex13 subunits respectively account for about 25% and 17% of GABAA receptors in the rat. Subtype assemblies containing an xcex15 subunit are primarily hippocampal and represent about 4% of receptors in the rat.
A characteristic property of some GABAA receptors is the presence of a number of modulatory sites, of which the most explored is the benzodiazepine (BZ) binding site through which anxiolytic drugs such as diazepam and temazepam exert their effect. Before the cloning of the GABAA receptor gene family, the benzodiazepine binding site was historically subdivided into two subtypes, BZ1 and BZ2, on the basis of radioligand binding studies. The BZ1 subtype has been shown to be pharmacologically equivalent to a GABAA receptor comprising the xcex11 subunit in combination with xcex22 and xcex32. This is the most abundant GABAA receptor subtype, representing almost half of all GABAA receptors in the brain.
Two other major populations are the xcex12xcex2xcex32 and xcex13xcex2xcex32/3 subtypes. Together these constitute approximately a further 35% of the total GABAA receptor repertoire. Pharmacologically this combination appears to be equivalent to the BZ2 subtype as defined previously by radioligand binding, although the BZ2 subtype may also include certain xcex15-containing subtype assemblies. The physiological role of these subtypes has hitherto been unclear because no sufficiently selective agoilists or antagonists were known.
It is now believed that agents acting as BZ agonists at xcex11xcex2xcex32, xcex12xcex2xcex32 or xcex13xcex2xcex32 subunits will possess desirable anxiolytic properties. The xcex11-selective GABAA receptor agonists alpidem and zolpidem are clinically prescribed as hypnotic agents, suggesting that at least some of the sedation associated with known anxiolytic drugs which act at the BZ1 binding site is mediated through GABAA receptors containing the xcex11 subunit. Accordingly, it is considered that GABAA receptor agonists which bind more effectively to the xcex12 and/or xcex13 subunit than to al will be effective in the treatment of anxiety with a reduced propensity to cause sedation. Also, agents which are antagonists or inverse agonists at xcex11 might be employed to reverse sedation or hypnosis caused by xcex11 agonists.
A number of dementing illnesses such as Alzheimer""s disease are characterised by a progressive deterioration in cognition in the sufferer. It would clearly be desirable to enhance cognition in subjects desirous of such treatment, for example for subjects suffering from a dementing illness. It is believed this can be done utilising compounds which are ligands for the GABAA xcex15 receptor subtype.
WO-A-9616954 mentions three thienylcyclohexanone derivatives in substituted by substituted arylaminocarbonyl on the thiophene ring as fungicides.
Van Rhee et al, J. Med. Chem., 1996, 39, 398-406 discloses related compounds as adenosine receptor antagonists which differ in having an ester group on the thiophene ring.
The present invention is directed to compounds according to Formula (I) or a pharmaceutically acceptable salt thereof that are GABA-A Alpha 5 ligands useful for enhancing cognition: 
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof. 
where A is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, arylC1-6alkyl, or aryl wherein the aryl group is optionally substituted by halogen, C1-6alkyl, CF3, CN, NO2 or NH2, NR1R10, S(O)pR1, heteroarylC1-6alkyl or heteroaryl where heteroaryl is a 5- or 6-membered heteroaromatic ring as defined for B below;
B is phenyl or a 5-membered ring having one or two unsaturations containing 1, 2, 3 or 4 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N, a 6-membered heteroaromatic ring containing 1, 2, 3 or 4 nitrogen atoms, each of which rings is optionally substituted by one or more substituents independently chosen from: cyano; C1-6alkyl; C1-6haloalkyl; halogen; S(O)rR4; COR5; and aryl, arylC1-6alkyl or a 5-membered ring having one or two unsaturations containing 1, 2, 3 or 4 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N wherein the aryl ring or 5-membered ring is optionally substituted by one, two or three substituents independently chosen from halogen, CF3, OCH3, nitro and cyano; and when a nitrogen ring atom is present it is optionally substituted by oxygen;
R1 is hydrogen; C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl or C3-6cycloalkenyl each of which is optionally substituted by amino, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkoxy, C1-6alkylaminocarbonyl, one, two or three hydroxy groups, one, two or three halogen atoms or a four, five or six-membered saturated heterocyclic ring containing a nitrogen atom and optionally either an oxygen atom or a further nitrogen atom which ring is optionally substituted by C1-4alkyl on the further nitrogen atom; aryl, aryl1-6alkyl, arylC2-6alkenyl or arylC2-6alkynyl optionally substituted on the aryl ring by halogen, nitro, cyano, C1-6alkylcarbonylamino, hydroxy or C1-6alkoxy; or a five-membered aromatic ring containing 1, 2, 3 or 4 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N, or a six-membered aromatic ring containing 1, 2, 3 or 4 nitrogen atoms, which ring is optionally substituted by halogen, C1-6alkoxy, C1-6alkylthio, aryl, C1-6alkyl, C2-6alkenyl or C2-6alkynyl;
R2 and R3 are independently hydrogen or C1-6alkyl or together with the carbon atom to which they are attached form a C3-8 cycloalkyl group;
R4 is hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, aryl or CH2(CO)mNR8R9;
R5 is NR6R7, C1-6alkyl or C1-6alkoxy;
R6 is independently as defined for R4;
R7 is aryl optionally substituted by halogen, nitro or cyano;
R8 is hydrogen, C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkenyl, C2-6alkenyl, C2-6alkynyl; arylC1-6alkyl, arylC2-6alkenyl or arylC2-6alkynyl optionally substituted on the aryl ring by halogen, nitro or cyano; thiophene or pyridine;
R9 is C1-6alkyl; C2-6alkenyl; C2-6alkynyl; or phenyl optionally substituted by one, two or three substituents independently chosen from halogen, CF3, OCH3, nitro and cyano;
R10 is hydrogen or C1-6 alkyl;
R14 is hydrogen or C1-6alkyl;
m is zero or 1;
p is zero, 1 or 2;
q is 1 or 2;
r is 0, 1 or 2;
s is 0, 1 or 2; and
t is 0, 1 or 2.
B may be phenyl or a 5-membered ring having one or two unsaturations containing 1, 2, 3 or 4 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N, or a 6-membered aromatic ring containing 1, 2, 3 or 4 nitrogen atoms, which ring is optionally substituted by one or more substituents independently chosen from: C1-6alkyl; C1-6haloalkyl; halogen; S(O)rR4; COR5; and aryl or arylC1-6alkyl wherein the aryl ring is optionally substituted by one, two or three substituents independently chosen from halogen, CF3, OCH3, nitro and cyano; and when a nitrogen ring atom is present it is optionally substituted by oxygen.
B is preferably an optionally substituted phenyl or optionally substituted 6-membered heteroaromatic ring. The optional substituents are preferably one or two groups independently chosen from halogen, C1-6alkyl, trifluoromethyl, cyano and an unsubstituted 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms chosen from O, N and S in which not more than one heteroatom is other than N. The optional substituent is preferably chosen from halogen, C1-6alkyl, trifluoromethyl and cyano.
B is most particularly optionally substituted phenyl or pyridine. In particular B may be pyridine and preferably pyridin-2-yl.
Thus when B is a heteroaromatic ring it may be a thiazole, pyrazole, pyrimidine, tetrazole, triazole, oxadiazole, oxazole, pyridine, imidazole or pyrazine which is unsubstituted or substituted by C1-6alkyl, halogen, SR4, COR5 or benzyl optionally substituted by halogen. When B is a 5- or 6-membered ring having one unsaturation it is preferably oxazolidinyl or imidazolinyl optionally substituted by halogen or C1-4alkyl.
Particular embodiments of B are (1-phenylsulphonyl)pyrazol-3-yl, 1-acetylpyrazol-3-yl, (3-ethoxycarbonyl)isoxazol-5-yl, (3-isopropyl)-1,2,4-oxadiazol-5-yl, imidazolin-2-yl, pyrazol-4-yl, 2-methyl-1,3,4-oxadiazol-5-yl, oxazolidin-2-yl, 2-methyltetrazol-5-yl, pyrazol-3-yl, 2-propyltetrazol-5-yl, thiazol-2-yl, 4-methyl-1,2,4-triazol-3-yl, (4-ethoxycarbonyl)thiazol-2-yl, (4-trifluoromethyl)thiazol-2-yl, (4-acetyl)thiazol-2-yl, (4-methyl)thiazol-2-yl, pyrrol-2-yl, pyrid-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 4-benzyl-1,2,4-triazol-3-yl, 1-methyl-1,2,4-triazol-3-yl, oxazol-2-yl, pyrazin-2-yl, pyrimidin-5-yl, 3-(N-methylaminocarbonyl)thiazol-2-yl, thiazol-5-yl, isoxazol-5-yl, pyrid-3-yl, pyrid-4-yl, 1,3,4-oxadiazol-5-yl and 1-methylsulphonylpyrazol-3-yl.
Other particular embodiments of B are pyridin-2-yl, 6-methyl pyridin-2-yl, thiazol-2-yl, 4-chlorophenyl, 4-fluorophenyl, 3-fluorophenyl, 4-trifluoromethylphenyl, 4-methylphenyl, 3-methylphenyl, pyrimidin-2-yl, pyridin-3-yl, 2-cyanophenyl, 5-chloropyridin-2-yl and 6-(thiazol-2-yl) pyridin-2-yl.
R1 is preferably C1-6alkyl, C2-6alkenyl or C3-6cycloalkyl each of which is optionally substituted by amino, di(C1-6alkyl)amino, hydroxy, C1-6alkoxy, C1-6alkylaminocarbonyl or one, two or three halogen atoms; aryl or aryl1-6alkyl optionally substituted on the aryl ring by halogen, C1-6alkylcarbonylamino or C1-6alkoxy; or a five-membered aromatic ring containing 1, 2 or 3 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N, or a six-membered aromatic ring containing 1 or 2 nitrogen atoms, which ring is optionally substituted by halogen, C1-6alkoxy, C1-6alkylthio, aryl or C1-6alkyl.
More preferably R1 is C1-6alkyl, C1-4alkenyl, or C3-6cycloalkyl each of which is optionally substituted by di(C1-4alkyl)amino, C1-4alkoxy, C1-4alkylaminocarbonyl, one or two hydroxy groups or three fluorine atoms; phenyl or phenylC1-4alkyl optionally substituted on the phenyl ring by chlorine, fluorine, C1-4alkoxy or C1-4alkylcarbonylamino; or a pyridine, thiophene, furan, pyrimidine, thiazole, imidazole, triazole or thiadiazole, each of which is unsubstituted or substituted by C1-4alkyl, phenyl, fluorine or C1-4alkylthio. In particular R1 is C1-6alkyl, phenyl, benzyl or pyridyl.
A may be C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, arylC1-6alkyl, aryl, S(O)pR1, heteroarylC1-6alkyl or heteroaryl where heteroaryl is a 5-membered ring having one or two unsaturations containing 1, 2, 3 or 4 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N, or a 6-membered aromatic ring containing 1, 2, 3 or 4 nitrogen atoms, which ring is optionally substituted by one or more substituents independently chosen from: C1-6alkyl; C1-6haloalkyl; halogen; S(O)rR4; COR5; and aryl or aryl C1-6alkyl wherein the aryl ring is optionally substituted by one, two or three substituents independently chosen from halogen, CF3, OCH3, nitro and cyano; and when a nitrogen ring atom is present it is optionally substituted by oxygen.
When A is not S(O)pR1 it is preferably C1-6alkyl, C2-6alkenyl or C3-6cycloalkyl. A may be C1-6alkyl such as ethyl.
A is preferably C1-6alkyl, C2-6alkenyl, arylC1-6alkyl or aryl wherein the aryl group is optionally substituted by a halogen atom or a C1-6alkyl group, a 5- or 6-membered heteroaromatic ring optionally substituted by a halogen atom or C1-6alkyl, NHR1 or SR1.
Particular embodiments of A include ethyl, 1,1-dimethylethyl, cyclopropyl, thiazol-2-yl, ethylthio, benzyl, phenyl, methylthio, ethenyl, phenylamino, pyridin-2-ylamino, phenylthio, pyrid-2-yl, benzylthio, oxazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl, thiazol-5-yl, 4-chlorophenyl, 4-methylthiazol-2-yl, 3-chlorophenyl and 2-chlorophenyl.
Particular embodiments of A are phenyl, cyclohexyl, 2-methylprop-1-enyl, methylthio, ethyl, isopropyl, propyl, cyclobutyl, but-3-enyl, cyclopropyl, methanesulphonyl, methyl, benzyl, methanesulphinyl, (1,1-dimethylethyl)thio, pentylthio, (4-methyl-1,2,4-triazol-3-yl)thio, hexylthio, benzylamino, (3-imidazol-1-ylpropyl)amino, (pyrid-2-yl)amino, 2-methylprop-1-yl, [3-(4-methylpiperazin-1-yl)propyl]amino, methylamino, (2-hydroxyethyl)amino, azetidin-1-yl, tert-butylamino, isopropylthio, (2-hydroxyethyl)thio, methoxy, dimethylamino, cyclobutoxy, phenoxy, butylthio, (3-chloropropyl)thio, (2-phenylethyl)thio, propylthio, (2-methylbutyl)thio, (2,2,2-trifluoroethyl)thio, (1-methylpropyl)thio, (4-chlorophenyl)thio, (3-fluorophenyl)thio, (4-acetylaminophenyl)thio, (4-methoxyphenyl)thio, (1-methylimidazol-2-yl)thio, (thiophen-2-yl)thio, (imidazol-2-yl)thio, (4-phenylthiazol-2-yl)thio, (1,2,4-triazol-3-yl)thio, (5-methyl-1,3,4-thiadiazol-2-yl)thio, (5-methylthio-1,3,4-thiadiazol-2-yl)thio, benzylthio, cyclopentylthio, (2-methylpropyl)thio, (furan-2-ylmethyl)thio, (2-hydroxy-1-methylpropyl)thio, (2,3-dihydroxypropyl)thio, (2-hydroxypropyl)thio, ((N-methylaminocarbonyl)methyl)thio, (pyrid-4-yl)thio, (pyrimidin-2-yl)thio, (thiazol-2-yl)thio, prop-2-enylthio, (pyrid-2-yl)thio, ethylthio, phenylthio, (N,N-dimethyl-2-aminoethyl)thio, (2-methoxyethyl)thio, (furan-2-ylmethyl)amino, (2-methylpropyl)amino, propylamino, (2-methoxyethyl)amino, cyclopropylamino, isopropylamino, ethylamino, cyclobutylamino and isopropoxy.
When A is heteroaryl it may be a thiazole, pyrazole, pyrimidine, tetrazole, triazole, oxadiazole, oxazole, pyridine, imidazole or pyrazine.
R2 and R3 are preferably independently chosen from hydrogen, methyl and propyl or are attached to the same carbon atom and together with that atom form a C3-6cycloalkyl group. Alternatively R2 and R3 are independently chosen from hydrogen and methyl. R2 may be hydrogen with R3 being hydrogen, methyl or isopropyl. Preferably both are methyl. Preferably R2 and R3 are geminal to each other, preferably at the 6-position, i.e. beta to the carbonyl group in formula I.
R4 may by hydrogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, aryl or CH2(CO)mNR8R9. R4 is preferably hydrogen, C1-4alkyl or CH2(CO)mNR8R9, more preferably hydrogen, methyl or CH2CONR8R9 and most preferably methyl or CH2CONR8R9.
R5 is preferably methyl, methoxy, ethoxy or NR6R7 and most preferably methyl, ethoxy or NR6R7.
R6 may be hydrogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, aryl or CH2(CO)mNR8R9. R6 is preferably hydrogen or C1-4alkyl and most preferably hydrogen.
R1 is preferably phenyl unsubstituted or substituted by halogen, nitro or cyano, more preferably optionally substituted by halogen, such as chlorine.
R8 is preferably hydrogen or C1-6alkyl and most preferably hydrogen.
R9 is preferably C1-6alkyl or phenyl unsubstituted or substituted by one, two or three substituents independently chosen from halogen, nitro and cyano, more preferably C1-6alkyl or phenyl optionally substituted by one or two substituents independently chosen from halogen and nitro and most preferably tert-butyl or phenyl optionally substituted with one or two substituents chosen from chlorine and nitro, such as 4-chlorophenyl.
R10 is preferably hydrogen or methyl, particularly hydrogen.
R14 is generally hydrogen or C1-4alkyl and most preferably hydrogen.
m is preferably 1.
p is preferably zero or two, most preferably zero.
q is preferably 1.
r is preferably 1.
s is preferably 0 or 1. s may be 1. s may be 0.
t is preferably 0 or 1. t may be 1. t may be 0.
A specific Example of a compound according to the present invention is:
6,6-dimethyl 3-ethyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one and the pharmaceutically acceptable salts thereof.
Further specific Examples of compounds according to the present invention are:
6,6-dimethyl-3-(1,1-dimethylethyl)-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
3-cyclopropyl-6,6-dimethyl-1-pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
3-ethyl-6,6-dimethyl-1-(pyrimidin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-3-ethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-3-ethyl-1-(3-fluorophenyl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-3-ethyl-1-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-3-ethyl-1-(4-methylphenyl)-4,5,6,7-tetrahydroindol-4-one;
1-(4-chlorophenyl)-6,6-dimethyl-3-ethyl-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-3-ethyl-1-(4-fluorophenyl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-3-ethyl-1-(3-methylphenyl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-3-methylthio-1-(pyridin-2-y1)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-3-ethylthio-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-3(phenylmethyl)thio-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-1-pyridin-2-yl)-3-(thiazol-2-yl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-3-phenyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-1-(pyridin-2-yl)-3-pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-1-(pyridin-2-yl)-3-vinyl-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-3-phenylmethyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-3-(oxazol-2-yl)-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-1-(pyridin-2-yl)-3-(thiazol-5-yl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-3-phenylamino-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-1-(pyridin-2-yl)-3-(pyridin-2-ylamino)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-3-ethyl-1-(6-methylpyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-3-(4-methylthiazol-5-yl)-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
3-(4-chlorophenyl)-6,6-dimethyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
3-(3-chlorophenyl)-6,6-dimethyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
3-(2-chlorophenyl)-6,6-dimethyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-1-(pyridin-3-yl)-3-(thiazol-2-yl)-4,5,6,7-tetrahydroindol-4-one;
1-(5-chloropyridin-2-yl)-6,6-dimethyl-3-(thiazol-2-yl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-3-(thiazol-2-yl)-1-(6-(thiazol-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
1-(2-cyanophenyl)-6,6-dimethyl-3-(thiazol-2-yl)-4,5,6,7-tetrahydroindol-4-one; and the pharmaceutically acceptable salts thereof.
Further specific compounds of the present invention are:
6,6-dimethyl-3-ethyl-1-(6-methylpyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
6,6-dimethyl-3-(3-methylthiazol-5-yl)-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
3-(1,1-dimethylethyl)-6-methyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
3-ethyl-6-methyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one;
6-methyl-1-(pyridin-2-yl)-3-(thiazol-2-yl)-4,5,6,7-tetrahydroindol-4-one;
3-(1,1-dimethylethyl)-6-(2-methylethyl)-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one
1-(pyridin-2-yl)-3-(thiazol-2-yl)-4,5,6,7-tetrahydroindol-4-one; and the pharmaceutically acceptable salts thereof.
There is also provided a pharmaceutical composition comprising a compound of formula I according to the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
Preferably the compositions according to the present invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, by inhalation or insufflation or administration by transdermal patches or by buccal cavity absorption wafers.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil or soybean oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
Compositions of the present invention may also be presented for administration in the form of trans-dermal patches using conventional technology. The compositions may also be administered via the buccal cavity using, for example, absorption wafers.
In disorders associated with GABAA xcex1 receptors, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.
The present invention also provides a process for the preparation of a pharmaceutical composition which comprises adding a compound of formula (I) or a pharmaceutically acceptable salt thereof to a pharmaceutically acceptable excipient.
The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body, in particular for the treatment or prevention of conditions for which the administration of a cognition enhancing agent is desirable, such as Alzheimer""s disease.
The compounds of formula (I) are of potential value in the treatment or prevention of a wide variety of clinical conditions which can be alleviated by a ligand selective for GABAA receptors containing the xcex15 subunit. In particular, they are desirably inverse agonists of the xcex15 subunit.
Thus, for example, such a ligand can be used in a variety of disorders of the central nervous system. Such disorders include delirium, dementia and amnestic and other cognitive disorders. Examples of delirium are delirium due to substance intoxication or substance withdrawal, delirium due to multiple etiologies and delirium NOS (not otherwise specified). Examples of dementia are: dementia of the Alzheimer""s type with early onset which can be uncomplicated or with delirium, delusions or depressed mood; dementia of the Alzheimer""s type, with late onset, which can be uncomplicated or with delirium, delusions or depressed mood; vascular dementia which can be uncomplicated or with delirium, delusions or depressed mood; dementia due to HIV disease; dementia due to head trauma; dementia due to Parkinson""s disease; dementia due to Huntington""s disease; dementia due to Pick""s disease; dementia due to Creutzfeld-Jakob disease; dementia which is substance-induced persisting or due to multiple etiologies; and dementia NOS. Examples of amnestic disorders are amnestic disorder due to a particular medical condition or which is substance-induced persisting or which is amnestic disorder NOS. In particular the compounds of formula (I) may be of use in conditions which require cognition enhancement.
Where the compounds of the present invention are selective ligands for GABAA xcex12 or xcex13 subtype receptors they may be used in the treatment and/or prevention of a variety of disorders of the central nervous system. Such disorders include anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder; neuroses; convulsions; migraine; and depressive or bipolar disorders, for example single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders, and cyclothymic disorder.
The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a condition requiring the administration of a ligand selective for GABAA receptors containing the xcex15 subunit, in particular for conditions requiring cognition enhancement such as Alzheimer""s disease. Other conditions to be treated include cognition deficits due to traumatic injury, stroke, Parkinson""s disease, Downs syndrome, age related memory deficits, attention deficit disorder and the like.
There is also disclosed a method of treatment or prevention of a condition associated with GABAA receptors containing the xcex15 subunit in a subject suffering from or prone to such a condition which comprises administering to that subject a therapeutically or prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In particular there is disclosed the treatment and prevention of conditions which require the administration of a cognition enhancing agent, such as Alzheimer""s disease.
As used herein, the expression xe2x80x9cC1-6alkylxe2x80x9d includes methyl and ethyl groups, and straight-chained and branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl. Derived expressions such as xe2x80x9cC2-6alkenylxe2x80x9d, xe2x80x9cC2-6alkynylxe2x80x9d, xe2x80x9cC1-4alkylxe2x80x9d, xe2x80x9cC2-4alkenylxe2x80x9d and xe2x80x9cC2-4alkynylxe2x80x9d are to be construed in an analogous manner.
The expression xe2x80x9cC3-6cycloalkylxe2x80x9d includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. xe2x80x9cC5-6cycloalkenylxe2x80x9d, xe2x80x9cC3-8cycloalkylxe2x80x9d and xe2x80x9cC5-7cycloalkylxe2x80x9d are to be construed analogously.
Suitable 5- and 6-membered heteroaromatic rings include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, tetrazolyl, oxadiazolyl and thiadiazolyl groups. These rings also include thiazolyl and triazolyl groups.
The term xe2x80x9chalogenxe2x80x9d as used herein includes fluorine, chlorine, bromine and iodine, especially fluorine, chlorine and bromine.
The expression xe2x80x9carylC1-6alkylxe2x80x9d as used herein includes benzyl, phenylethyl, phenylpropyl and naphthylmethyl. xe2x80x9cArylC2-6alkenylxe2x80x9d, xe2x80x9carylC2-6alkynylxe2x80x9d and xe2x80x9cheteroarylC1-6alkylxe2x80x9d should be construed in an analogous fashion.
Typical aryl groups include phenyl and naphthyl. Preferably the aryl is phenyl.
For use in medicine, the salts of the compounds of formula (I) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
Where the compounds of formula (I) have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds of formula (I) possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
The present invention also provides a process for producing a compound of formula I which comprises reacting a compound of formula II with a compound of formula III: 
wherein R2, R3, A and B are as defined above and Hal is a halogen atom such as bromine, chlorine or fluorine, generally in a solvent such as DMF and in the presence of a strong base such as NaH, generally with heating to about 90xc2x0 C. for about 6 h. Alternatively the reaction may be carried out using CuBr in DMF in the presence of K2CO3 generally with heating to about 180xc2x0 C. for about 48 h.
The compound of formula II is prepared by decarboxylating a compound of formula IV: 
wherein R2 and R3 are as defined above by heating at about 100xc2x0 C. for about 45 minutes generally in the presence of an acid such as acetic acid and/or hydrochloric acid.
The compounds of formula IV is prepared by hydrolysing a compound of formula V: 
wherein R2 and R3 are as defined above generally by heating at reflux for about 6 h generally in the presence of a base such as KOH and a solvent such as ethanol and water. This reaction can also be performed by heating the compound of formula V in DMSO and H2O at about 150xc2x0 C. for about 18 h.
The compound of formula V is prepared by reacting a compound of formula VI with a compound formula VII: 
wherein A and R1 are defined above, generally with heating to about 100xc2x0 C. for about 1 h in a buffered solution such as acetic acid/sodium acetate in the presence of a catalyst such as zinc optionally in powdered form. This reaction can produce a compound of formula II directly when it is carried out at 150xc2x0 C.
The compound of formula VI is prepared by reacting a compound of formula VIII: 
wherein A and Rxe2x80x2 are as defined above, with sodium nitrite generally in the presence of an acid such as acetic acid in a solvent such as water at room temperature for about 1 h.
The compounds of formulae III, VII and VIII are either commercially available or can be made by the skilled person from commercially available compounds by known methods.
In an alternative process, a compound of formula II in which A is SR1, wherein R1 is as defined above, is prepared by reacting a compound of formula IX: 
wherein R2 and R3 are as defined above, with heating for about four hours in the presence of an acid such as trifluoroacetic acid, generally in a solvent such as ClCH2CH2Cl. The resulting product is a mixture of compounds of formulae II and IX which are then separated by conventional means.
The compound of formula IX is prepared by reacting a compound of formula X: 
wherein R2 and R3 are as defined above, with R1I, wherein R1 is as defined above, in the presence of a solvent such as methanol with a base as ROH for about 3 h at room temperature. The compound R1I is commercially available or may be made by methods known to the skilled person from commercially available compounds.
The compound of formula X is made by reacting a compound of formula XI: 
wherein R2 and R3 are as defined above, with bromine and KSCN in a solvent such as methanol at a temperature of from xe2x88x9230xc2x0 C. to room temperature.
The compound of formula XI can be made by reacting a compound of formula VII with a compound of formula XII: 
with paratoluensulphonic acid generally in a solvent such as toluene with heating for about 3 h, and then carrying out a Michael addition by heating at about 40xc2x0 C. for about 9 h with an acid such as HCl, preferably at 3N.
The compound of formula XII is commercially available or can be made by known methods from commercially available compounds.
Alternatively the compound of formula XI may be obtained commercially.
Alternatively a compound of formula I is produced by reacting a compound of formula XIII with a compound of formula XIV: 
wherein R2, R3, A and B are as defined above:
(i) where Z is Sn(Bu)3 in the presence of tetrakis(triphenylphosphene) palladium or dichlorobis(triphenylphosphine) palladium in a solvent such as dioxan generally with heating to reflux in a solvent such as dioxan or hexamethylphosphoramide for about 24 h to 48 h at about 70xc2x0 C.;
(ii) where Z is B(OH)2 in the presence of tetrakis(triphenylphosphene) palladium generally in a biphasic mixture of solvents such as ethylene glycol dimethyl ether and water and in the presence of a mild base such as Cs2CO3 or Na2CO3 at reflux for about 8 h; or in the presence of Cu(OAc)2 in a solvent such as DCM, in the presence of a base such as Et3N generally at room temperature;
(iii) where Z is NR10H in the presence of tris(dibenzylideneacetone)dipalladium generally with a base such as NaOtBu, a solvent such as toluene and a compound such as (R)-(+)-2,2xe2x80x2-bis(diphenylphosphino)-1,1-binaphthyl generally at reflux for about 3 h. (This last method produces compounds of formula I in which A is NR1R10).
The compound of formula XIII can be produced by reacting a compound of formula XV: 
wherein R2 and R3 are as defined above with a compound of formula III as defined above generally in the presence of a strong base such as NaH and in a solvent such as DMF for about 5 min.
The compound of formula XV can be produced by reacting a compound of formula XVI: 
wherein R2 and R3 are as defined above with a brominating agent such as N-bromosuccinimide generally in a solvent such as THF generally with cooling to about xe2x88x9278xc2x0 C. for about 1 h.
The compound of formula XVI can be produced by reacting a compound of formula XI as defined above with (iPr)3SiCl generally in a solvent such as DMF at about 0xc2x0 C. for about 1 h.
Compounds of formula XIV are commercially available or can be made by known by methods from commercially available compounds.
A compound of formula I may also be prepared by interconversion from another compound of formula I by known methods.
Compounds of formula I in which A is S(O)pR1 wherein p is one or two can be obtained by reacting a compound of formula I in which A is S(O)pR1 in which p is zero or one and R1 is as defined above with a stoichiometric quantity of mCPBA, generally in a solvent such as CH2Cl2: dioxan with cooling to about xe2x88x9278xc2x0 C.
It will be understood that the above transformations of S(O)pR1 are illustrative and other standard techniques known to the skilled person may alternatively be used.